Dissecting shared genetic susceptibility between gastroesophageal reflux disease and psychiatric disorders beyond body mass index

Gastroesophageal reflux disease (GERD) exhibits substantial comorbidity with psychiatric disorders, yet the biological basis underlying this relationship remains unclear. Here, we integrated large-scale GWAS meta-analysis, Mendelian randomization, Genomic Structural Equation Modeling, local genetic correlation analysis, and single-cell transcriptomic enrichment mapping to investigate the shared genetic architecture linking GERD, psychiatric disorders, and body mass index (BMI). GERD demonstrated strongest genetic overlap with internalizing psychiatric disorders, particularly major depressive disorder and post-traumatic stress disorder, whereas the relationship with BMI was comparatively weaker and lacked significant bidirectional causal effects. Genomic SEM further showed that GERD preferentially loaded onto an internalizing latent factor independent of obesity-related liability. At the cellular level, GERD-associated genetic signals localized predominantly to interoceptive and limbic brain systems involved in visceral sensation, stress responsivity, and autonomic regulation. Together, these findings support a distinct neuropsychiatric component underlying GERD susceptibility and implicate centrally mediated brain-gut mechanisms beyond metabolic dysfunction.